JPS6016428B2 - Pyrazolidine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to new and useful pyrazo 1'zine derivatives.

The pyrazolidine derivative of the present invention is a novel substance based on the literature, and is represented by the following general formula (1).

However, in the formula, RI represents a lower alkyl group such as methyl, ethyl, propyl, butyl, R2 represents a hydrogen atom or a lower alkyl group such as methyl, ethyl, propyl, butyl, and n represents an integer from 2 to 10. . Pyrazolidine derivatives are well known as antipyretic and analgesic drugs, and many derivatives have been proposed so far.

The present inventors have focused on the fibrinolytic activity of pyrazolidine derivatives, and have attempted to develop antithrombotic materials by binding or adsorbing pyrazolidine derivatives to the surface of polymeric substances. At present, pyrazolidine derivatives that have a functional group capable of binding to molecular substances and also have fibrinolytic activity are not well known.

As a result of repeated research on the synthesis of various pyrazolidine derivatives, the present inventors have synthesized a derivative represented by the general formula (1) which has a number of excellent features as will be explained later.

Examples of the novel pyrazolidine derivatives of the present invention include the following.

3-(3,5-dioxo-1,2-diphenyl-4-n
-butyl-4-pyrazolidyl)propionic acid,
Methyl 3,5-dioxo1,2-diphenyl-4-n-butyl-4-pyrazolidyl)propionate'11-(
3,5-dioxo-1,2-diphenyl-4-n-butyl-4-pyrazolidyl)undecanoic acid, 11-(3.5
-dioxo-1,2-diphenyl-4-n-butyl-4
-pyrazolidyl) methyl undecanoate.

All of the pyrazolidine derivatives of the present invention are characterized by not only excellent antipyretic and analgesic effects, but also particularly excellent fibrinolytic activity and excellent antithrombotic properties. Although the pyrazolidine derivative of the present invention can be synthesized by various methods, the following method is particularly desirable.

That is, the derivative represented by the following general formula (0) [wherein RI is the same as in general formula (1)] can be used, for example, as metallic sodium, metallic potassium, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, It is reacted with equimolar moles of an alkaline substance such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, and the resulting alkali salt is expressed by the following general formula (m)X(C ratio)nC02R2 (
m) [In the formula, R2 and n are the same as in the general formula (1), and X represents a halogen element such as fluorine, chlorine, bromine, or iodine] to produce the desired general A derivative represented by formula (1) is synthesized.

Further, the conductor represented by the general formula (1) of the present invention can be prepared by halogenating the compound represented by the general formula (0) in the presence of an alkali compound in a solvent such as alcohol. It can also be synthesized by reacting with fatty acids. The above reaction is usually carried out in a solvent.

Examples of solvents that can be used include water, methanol, ethanol, n-pro/gnol, isopro/gnol,
Examples include benzene, acetone, dioxane, ethylene chloride, chloroform, ethyl acetate, pyridine, and other general organic solvents that do not participate in the reaction, but if necessary, these solvents may be used in combination. The pyrazolidine derivative of the present invention can be easily coated on any polymer compound such as nylon, polyester, polyethylene, polyvinyl chloride, latex, polypropylene, polystyrene, silicone, etc. Artificial blood vessels, catheters, artificial valves, artificial hearts, artificial lungs,
By coating an artificial kidney or the like, it can impart excellent antithrombotic properties.

In addition, the pyrazolidine derivative of the present invention may be administered orally by sprinkling it on bran such as sucrose, glucose, fructose, or starch if the amount is appropriate, or it may be dissolved in salt form in sterile distilled water and administered intravenously. You can also. Example 1 (RI: n-butyl, R2: methyl, n: 2) 2.8 g of phenylptazone and 0.36 g of sodium hydroxide were dissolved in 40 g of ethanol, and then B-frompropionic acid was added to this solution. After 1.5 hours of methyl was slowly added, the mixture was refluxed for 3 hours.

After filtering the produced sodium bromide, the ethanol was distilled off and the resulting residue was purified by silica gel column chromatography to obtain oily 3-(3,5-dioxo-1,2-diphenyl-4- 2.3 ml of methyl n-butyl-4-pyrazolidyl)propionate was obtained. In addition, as a by-product, 5-(2-methoxycarbonyl)
Ethoxy 1,2-diphenyl-4-n-butyl-3-pyrazolone was also obtained. Identification of synthesized compounds is performed using NMR, gas chromatography, and mass spectrometry (GC-MS).
).

3-(3,5-dioxo-1,2) in deuterated chloroform
The NMR spectrum of methyl -diphenyl-4-n-butyl-4-pyrazolidyl)propionate is 60.9,61
．． 3-1.6, 61.9-2.1 (group) butyl, 62
．． Ethylene (-CQCH2CQCH3) at 4 (cape), 6
Ester methyl to 3.6 (singlet mother H), 67
．． 3 (si-enhanced blood) showed a phenyl signal. In addition, the by-product 5-(2-methoxycarbonyl)
The NMR spectrum (in CDC13) of ethoxy 1,2-diphenyl-4-n-butyl-3-pyrazolone has butyl at 60.9,61-3 to 1-6,62-4 (cape), and 62.5 (Wplet) adjacent to estel. Methylene (1○-CQCQC02CH3), 63.6 (sin
get ester methyl, 64.4 (roiple)
t) to 0-methylene (-0-CH2C ratio C02CH3
), 67.3 (singlet blood) showed a phenyl signal. GC-MS shows parent peak at m/e394,
Demethoxy to m/e364, debutyl to m/e338,
There is a phenyl peak at m/e77, m/e183,
A series of peaks due to cleavage of the pyrazolidine ring were shown at 119, 105, and 93. When compared with the by-product 5-(2-methoxycarbonyl)ethoxy-1,2-diphenyl-4-n-butyl-3-pyrazolone, there is a difference in the elimination of methyl propionate, with the bond to carbon being more likely to be eliminated. Although the cleavage patterns of the pyrazolidine rings were very similar, only the peak intensities were different. Based on the NMR and GC-MS results, the synthesized compound was 3-(3,5-dioxo-1,2-diphenyl-4).
It was identified as methyl -n-butyl-4-pyrazolidyl)propionate.

Example 2 (RI: n-butyl, R2: hydrogen, n: 2) 6.5 mm of phenylptazone and 0.84 mm of sodium hydroxide were dissolved in 60 mm of isopropanol, and then 3-prompropion was added to this solution. 3.2 hours of acid was added and the mixture was refluxed for 3 hours.

After heating the produced sodium bromide in a furnace for 8U, isopropanol was distilled off and the resulting residue was dissolved in chloroform.
The chloroform solution was reduced to 0. Washed with state hydrochloric acid. The chloroform solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain oily 3-(3,5-dioxo-1,
1.5 hours of 2-diphenyl-4-n-butyl-4-pyrazo-1'dylpropionic acid was obtained. The synthesized compound was identified by NMR and GC-MS.

Heavy black. The NMR spectrum in form showed a carboxyl proton signal at 611.0 (singlet IH) instead of 63.6 (singlet 3H) of ester methyl of Example 1. Furthermore, the NMR spectrum of this compound obtained by methylesterifying it with diazomethane in ether matched well with the NMR spectrum of the compound of Example 1. GC-MS has parent peak at m/e 0, m/e3
A series of peaks were shown due to removal of OH at 63, removal of butylation at m/e 324, phenyl at m/e 77, and cleavage of the pyrazolidine ring at m/e 183, 119, 10, and 93. NMR
The compound synthesized from the results of GC-MS and GC-MS was 31 (3
, 5-dioxo-1,2-diphenyl-4-n-butyl-4-pyrazolidyl)propionic acid.

Example 3 (RI: n-butyl, R2: methyl, n: 10) 2.8 mm of phenylbutazone and 0.36 mm of sodium hydroxide were dissolved in 40 mm of inpropyl alcohol, and then 11- 2.4 hours of methyl promoundecanoate was added and the mixture was refluxed for 3 hours.

After the produced sodium bromide was filtered off, the isopropanol was removed and the resulting residue was purified by silica gel column chromatography to obtain a highly viscous oily 11-(3,5
-dioxo 1,2-diphenyl-4-n-phthyl-4
2.7 ml of methyl (pyrazolidyl) undecanoate was obtained.
The synthesized compound was analyzed by NMR and G as in Examples 1 and 2.
Confirmed by C-MS. Reference Example 4 wt % dioxane solutions of the compounds obtained in Examples 1 to 3 were each circulated at a flow rate of 50 secretions/skin in a nylon 6 tube with an inner diameter of 3 holes and an outer diameter of 5 ribs at room temperature for 5 hours.

The tube was washed with dioxane and then dried under reduced pressure. The thrombus formation time of each of the nylon 6 tubes coated with the pyrazolidine derivative of the present invention thus obtained was 45 minutes or more. On the other hand, the thrombus formation time for the same internally treated nylon 6 tube or medical silicone tube was 1 minute and 2 minutes, respectively.

Claims (1)

[Claims] 1 General formula (I) ▲ Includes mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents a lower alkyl group, R^2 represents a hydrogen atom or a lower alkyl group, and n is represents an integer from 2 to 10.) A pyrazolidine derivative represented by: 2. The pyrazolidine derivative according to claim 1, which is a compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼. 3. A pyrazolidine derivative according to claim 1, which is a compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼.